Abstract 4537: SBT6050, a HER2-directed TLR8 ImmunoTAC™therapeutic, is a potent human myeloid cell agonist that provides opportunity for single agent clinical activity

Abstract

Abstract SBT6050, a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody that binds an epitope distinct from trastuzumab, is designed for systemic delivery and tumor-localized activation of human myeloid cells in the presence of moderate and high HER2-expressing tumor cells. Many solid tumors, including those expressing HER2, are refractory to immunotherapy due to immune-suppressive mechanisms, loss of HLA, low neoantigen availability, and/or minimal T cell infiltrates. These tumors frequently contain abundant populations of tumor-associated myeloid cells. Activation of these cells through TLR agonism has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. Unlike other endosomal TLRs such as TLR7 and TLR9, TLR8 is highly expressed in human myeloid cells known to be prevalent in human tumors such as conventional DCs and macrophages. TLR8's restricted myeloid cell expression removes the risk of inducing T cell death or tumor cell proliferation as described for other innate immune activators such as STING. Agonism of TLR8 in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including proinflammatory cytokine production, repolarization of suppressive myeloid cells and the priming of CTL responses. These functions cannot be replicated by a potent TLR7 agonist or with clinical agents such as resiquimod that agonize TLR7 and only weakly engage TLR8. Here we present data demonstrating the superiority of SBT6050 at activating human myeloid cells compared to HER2 antibody conjugates that use either a selective TLR7 agonist or resiquimod. In vitro studies with human immune cells show that SBT6050 potently induces multiple anti-tumor immune activities, including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. Our data indicate the favorable profile of SBT6050 is likely due to efficient engagement of TLR8 in conjugate form and TLR8's unique expression profile, and not due to differences in the potency of the small molecule payloads. Using an SBT6050 mouse surrogate we show in vivo evidence for intratumoral TLR agonist activation of several myeloid driven anti-tumor pathways leading to curative single agent efficacy in both a T cell-excluded syngeneic tumor model and a xenograft model lacking T, B and NK cells. Collectively, these data demonstrate that SBT6050 displays an attractive functional profile unachievable with agonist-based antibody conjugates directed against other innate immune receptors. These data also highlight the potential for SBT6050 to be clinically active as a monotherapy. SBT6050 is projected to enter the clinic in 2020 for patients with moderate or high HER2-expressing tumors. Citation Format: Michael R. Comeau, Ty Brender, Monica Childs, Jamie Brevik, Damion Winship, Heather Metz, Jenny Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Brenda Stevens, Sean W. Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum, Valerie Odegard. SBT6050, a HER2-directed TLR8 ImmunoTAC™therapeutic, is a potent human myeloid cell agonist that provides opportunity for single agent clinical activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4537.